Attention Deficit Disorder with Hyperactivity Symptoms in Early-Treated Phenylketonuria Patients.

Section Title Objectives To assess the presence of symptoms consistent with Attention Deficit Disorder with Hyperactivity (ADHD) in all patients with early-treated phenylketonuria (PKU) in the State of Santa Catarina in southern Brazil. Materials & Methods All of the patients diagnosed with PKU by newborn-screening tests, with ages varying from 6 to 18 years and who started treatment before 60 days of life and presented phenylalanine levels consistently below 6 mg/dL throughout treatment, were included. The subjects were invited to complete a questionnaire that collected sociodemographic, gestational and clinical data. ADHD symptoms were assessed using the revision of the Swanson, Nolan and Pelham Questionnaire. Results A total of 34 patients were evaluated, who were 53% male and 94% white and had an average age of 12 years, and 15% were born premature. According to the Swanson, Nolan and Pelham Questionnaire, 13 patients (38%) met the diagnostic criteria for ADHD, with 2 patients having the inattentive type, 6 patients having the hyperactive or impulsive type and 1 patient having the oppositional defiant disorder type. Conclusion: Although the patients with PKU were regularly treated from birth, there was a high prevalence of symptoms consistent with ADHD. A pathophysiological interface that involves the dopamine metabolic pathway may exist between the two conditions.

Neurobiologically, Attention Deficit Disorder with Hyperactivity (ADHD) appears to be closely related to the dopaminergic neurotransmission system. DA is a neurotransmitter that has a key role in attention and concentration. Moreover, cortical dopaminergic pathways act in mediating cognitive functions, such as learning, maintaining attention and concentration (3,4). Individuals with PKU and ADHD seem to have low levels of DA in common, causing the hypodopaminergic state found in both disorders to be a possible link between these two conditions, and individuals with PKU could have a greater predisposition to the development of ADHD.
The prefrontal cortex is especially sensitive to low levels of DA, and it is speculated that even moderate elevations of Phe may result in low levels of DA in the central nervous system. ADHD and PKU are therefore theoretically linked by low levels of available DA in the prefrontal cortex (7)(8)(9). Many authors have questioned the existence of a pathophysiological relationship between PKU and ADHD and emphasize the importance of additional studies that may further elucidate the relationship between these entities (10). Despite the existence of theoretical background, there are few reports studying the linkage between ADHD and PKU. The aim of this study was to verify the presence of ADHD symptoms in patients with early-treated PKU.  (11).

Materials & Methods
Every PKU patient who started treatment after 60 days of age, who failed to maintain Phe levels below 6 mg/dL or who failed to adhere to regular medical follow-ups were excluded.

Procedures
During regular medical appointments, the patients' legal representatives, who were usually the patients' parents, were asked to complete questionnaires regarding epidemiological data (age, gender, According to the DSM-IV, for the diagnosis of ADHD, it is essential to identify the presence of symptoms consistent with ADHD that present before the age of 7 in at least two different contexts (e.g., at home and at school) and are associated with evident damage in school, social or family life and to determine whether those existing symptoms are not better explained by the presence of another psychiatric disorder. A confirmation of the diagnosis can only be achieved through proper neurological or psychiatric investigation (14).
In this study, the Portuguese version SNAP-IV was used for the standardization of ADHD symptoms (12).
The SNAP-IV is a questionnaire containing 26 items aimed at parents and teachers and related to ADHD symptoms. The items are subdivided into scales related to the symptoms of inattention (items 1 to 9), hyperactivity or impulsivity (items 10 to 18) and oppositional defiant disorder (ODD; 19 to 26). Each question about a symptom can be answered in four different ways: "not at all", "just a little", "quite a bit" or "very much". Only the presence of six or more responses of "quite a bit" or "very much" on the items related to inattention and/or hyperactivity indicate the presence of ADHD symptoms (12).
When there are at least six items marked as "quite a bit" or "very much" among items 1 to 9 of the SNAP-IV, there are more symptoms of inattention than expected in a child or adolescent, and the individual has symptoms suggestive of the inattentive subtype of ADHD (12,15).
If there are at least six items marked as "quite a bit" or "very much" among items 10 to 18 of the SNAP-IV, then there are more symptoms of hyperactivity or impulsivity than expected in a child or adolescent, thus identifying the hyperactive or impulsive subtype of ADHD (12,15,16). We included items related to the DSM-IV criteria for ODD, corresponding to items 19 to 26 of the SNAP-IV, because ODD increases the risk of the emergence of antisocial behavior in children and adolescents and is often present in those individuals with ADHD (12).

Statistical Analysis
Statistical analysis was performed using EpiInfo

Results
In 2012, the State of Santa Catarina had a total of 142 patients with a confirmed diagnosis of PKU, of which 77 were diagnosed and treated from birth.
Among those individuals, a total of 34 patients were considered to be eligible for our study.

Sociodemographic and Epidemiological Aspects
Regarding the city of birth, there is a homogeneous distribution across the State of Santa Catarina, with the 34 PKU patients spread across all regions of the state, as observed in detail in Figure 1.
Regarding the epidemiological variables, as shown in Table 1, there was a slight predominance of men (53%) and white patients (94%) in the sample.
The mean age was 12 years. Considering children who were 12 years old or less and adolescents who were older than 12 years old, our sample consisted of 19 children (56%) and 15 adolescents (44%).
Regarding family income, we observed that most parents of PKU patients earned up to five times the minimum wage.
It was observed that only 2 patients had a history of parental consanguinity. In one case, the parents were cousins , and in another, the parents were an uncle and n iece. Most patients were born by cesarean deli v ery and at term. Most patients received regular treatment, consisting of a specific diet for PKU (foods with Phe restriction) and using special protein formulas (with Phe restriction). A minority of patients only received dietary treatment but still managed to successfully keep their blood Phe levels below 6 mg/dL (Table 1).

Education Level
Regarding the education of the PKU patients, 26 patients (76% ) were up-to-date with their ageappropriate class, without grade repetition.
Concerning the higher parents' education, half of the parents had a complete or incomplete university education ( Table 2).

ADHD
Taking into account the criteria for clinical symptoms suggestive of ADHD, i.e., considering six or more answers of "quite a bit" or "very much" on the SNAP-IV questionnaire as positive for ADHD, 13 patients (38%) in our sample showed symptoms suggestive of ADHD.
Among the patients with symptoms suggestive of ADHD, 2 patients (15%) could be classified as having the inattentive subtype of ADHD, whereas 6 patients (46%) could be classified as having the hyperactive or impulsive ADHD subtype according to the SNAP-IV. Only 1 patient fit the ODD criteria and also showed symptoms suggestive of ADHD. A statistical comparison of the data can be viewed in detail in Table 3. When comparing the prevalence of symptoms suggestive of ADHD in relation to gender, we found that 6 patients (46%) were female, whereas 7 patients (54%) were male. There was no statistical significant relationship between sex and the prevalence of positive symptoms of ADHD.
Thus, in this case, prematurity was not related to the increased presence of symptoms suggestive of ADHD (Table 3).
Regarding parental consanguinity and positive symptoms of ADHD, we found that all patients with consanguineous parents (n=2) had symptoms consistent with ADHD. Of the 32 patients whose parents were not consanguineous, 11 subjects (34%) had symptoms consistent with ADHD. When the PR between symptoms consistent with ADHD and the presence or absence of consanguineous parents was calculated, it was observed that the prevalence of ADHD symptoms was approximately three times higher in patients with consanguineous parents than in patients without consanguinity (PR = 2.9, 95% CI 1.8 to 4.7, Table 3).
Regarding the type of delivery, 5 patients (38%) with symptoms suggestive of ADHD were born vaginally, and 8 (62%) were born through a cesarean. The ADHD diagnosis prevalence rate of those individuals who underwent a normal birth compared with those patients who were born through a cesarean delivery was 1.14 (95% CI 0.48 to 2.73), and there was no statistical significant association between the type of delivery and ADHD diagnosis (Table 3).  Adapted from "Guia Turístico e Cultural do Estado de Santa Catarina". Web site: http://www.sctur.com.br/

Discussion
Individuals with PKU and ADHD seem to have low levels of DA in common, causing the hypodopaminergic state found in both disorders to be a possible link between these two conditions, and individuals with PKU could have a greater predisposition to the development of ADHD.
For the first time in Brazil, this study assessed the relationship between PKU, a rare genetic and neurometabolic disease, with ADHD, the most common neurobehavioral condition affecting the pediatric population. We believe that these two conditions can be comorbid.
The term "comorbidity" was initially described by for ADHD, with a prevalence that was 2.5 times higher than in the general population in this study.
All children were diagnosed with ADHD of the inattentive type. The results indicated that high levels of Phe are toxic to the neurological system that manages the executive and cognitive functions and that the duration of exposure to high levels of Phe can affect the expression of ADHD symptoms (23,24).